Substituted 2-carba-3,5-dicyano-4-aryl-6-aminopyridines and the use of the same as selective ligands of the adenosine receptor

Abstract

This application relates to compounds of the formula wherein the groups R 1 –R 6 are as defined in the specification and claims, and to a pharmaceutical composition containing the same, and to a method of using the same in treatment of cardiovascular disorders.

1. A compound of the formula (I) 
       
         
           
           
               
               
           
         
         in which 
         R 1 , R 2  and R 3  independently of one another represent (C 1 –C 8 )-alkyl which may be substituted up to three times by hydroxyl, (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl, (C 2 –C 4 )-alkenyl, (C 2 –C 4 )-alkynyl, halogen or (C 6 –C 10 )-aryloxy, (C 6 –C 10 )-aryl which may be substituted up to three times by halogen, nitro, (C 1 –C 4 )-alkoxy, carboxyl, (C 1 –C 4 )-alkoxycarbonyl or mono- or di-(C 1 –C 4 )-alkylamino, (C 1 –C 8 )-alkoxy which may be substituted by hydroxyl, (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl, (C 2 –C 4 )-alkenyl, (C 6 –C 10 )-aryl, 5- or 6-membered heteroaryl having up to three heteroatoms selected from the group consisting of N, O and S, (C 6 –C 10 -aryloxy, halogen, cyano, (C 1 –C 4 )-alkoxycarbonyl, (C 1 –C 4 )-alkanoyloxy, amino or mono- or di-(C 1 –C 4 )-alkylamino, hydrogen, hydroxyl, halogen, nitro, cyano or —NH—C(O)—R 7 , 
         in which
 R 7  represents (C 1 –C 8 )-alkyl which may be substituted by hydroxyl or (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl or (C 6 –C 10 )-aryl which may be substituted up to three times by, independently of one another, by halogen, nitro, (C 1 –C 4 )-alkoxy, carboxyl, (C 1 –C 4 )-alkoxycarbonyl or mono- or di-(C 1 –C 4 )-alkylamino, 
 
         or 
         R 1  and R 2  are attached to adjacent phenyl ring atoms and, together with the two ring carbon atoms, form a 5- to 7-membered saturated or partially unsaturated heterocycle having one or two heteroatoms selected from the group consisting of N, O and S which may be substituted by (C 1 –C 4 )-alkyl or oxo, 
         R 4  represents hydrogen, (C 1 –C 8 )-alkyl which may be substituted by hydroxyl, (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl, (C 6 –C 10 )-aryl, 5- or 6-membered saturated or partially unsaturated heterocyclyl having up to three heteroatoms selected from the group consisting of N, O and S or 5- to 10-membered heteroaryl having up to three heteroatoms selected from the group consisting of N, O and S, or (C 3 –C 7 )-cycloalkyl which may be substituted by hydroxyl or (C 1 –C 8 )-alkyl, 
         R 5  represents (C 1 –C 4 )-alkyl or (C 1 –C 4 )-alkoxy which may be mono- or disubstituted, independently of one another, by hydroxyl, (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl, (C 6 –C 10 )-aryl or 5- to 10-membered heteroaryl having up to three heteroatoms selected from the group consisting of N, O and S, where aryl and heteroaryl for their part may be substituted by halogen, (C 1 –C 4 )-alkyl, (C 1 –C 4 )-alkoxy, amino, mono- or di-(C 1 –C 4 )-alkylamino, nitro, cyano, trifluoromethyl or hydroxyl, or (C 2 –C 4 )-alkenyl, 
         R 6  represents (C 1 –C 8 )-alkyl which may be substituted by hydroxyl, (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl, (C 2 –C 4 )-alkenyl, —CO—O—R 8 , (C 6 –C 10 )-aryl or 5- to 10-membered heteroaryl having up to three heteroatoms selected from the group consisting of N, O and S where aryl and heteroaryl for their part may be substituted by halogen, (C 1 –C 4 )-alkyl, (C 1 –C 4 )-alkoxy, amino, mono- or di-(C 1 –C 4 )-alkylamino, nitro, cyano, trifluoromethyl or hydroxyl, (C 3 –C 7 )-cycloalkyl or —CO—O—R 8 ,
 in which 
 R 8  represents hydrogen, (C 1 –C 8 )-alkyl which may be substituted by hydroxyl or (C 1 –C 4 )-alkoxy, (C 3 –C 7 )-cycloalkyl or (C 6 –C 10 )-aryl which may be substituted up to three times, independently of one another, by halogen, nitro, (C 1 –C 4 )-alkoxy, carboxyl, (C 1 –C 4 )-alkoxycarbonyl or mono- or di-(C 1 –C 4 )-alkylamino, 
 or 
 
         R 5  and R 6  together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated ring which may contain one or two heteroatoms selected from the group consisting of N, O and S in the ring and which may be mono- to trisubstituted, independently of one another, by oxo, fluorine, chlorine, bromine, hydroxyl, (C 1 –C 6 )-alkyl or (C 1 –C 6 )-alkoxy,
 or a salt, a hydrate, a hydrate of a salt or a solvate thereof. 
 
       
     
     
       2. The compound as claimed in  claim 1 
 in which 
 R 1  and R 2  independently of one another represent hydrogen, (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkoxy which may be substituted by hydroxyl, (C 1 –C 4 )-alkoxy, (C 1 –C 4 )-alkanoyloxy or cyclopropyl, hydrogen, hydroxyl, fluorine, chlorine, nitro or —NH—C(O)—CH 3  
 or 
 
 R 1  and R 2  are attached to adjacent phenyl ring atoms and represent a group —O—CH 2 —O—or —O—CH 2 —CH 2 —O—, 
 R 3  represents hydrogen, 
 R 4  represents hydrogen, (C 1 –C 4 -alkyl which is substituted by hydroxyl, (C 1 –C 4 )-alkoxy or cyclopropyl, or represents cyclopropyl, 
 R 5  represents (C 1 –C 4 )-alkyl which may be mono- or disubstituted, independently of one another, by (C 3 –C 6 )-cycloalkyl, phenyl, which for its part may be substituted by fluorine, trifluoromethyl or (C 1 –C 4 )-alkoxy, pyridyl, furyl or thienyl, or (C 2 –C 4 )-alkenyl, 
 and 
 R 6  represents (C 1 –C 4 )-alkyl or —CO—O—R 8  wherein R 8  is (C 1 –C 4 )-alkyl 
 or 
 R 5  and R 6  together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated ring which may contain a heteroatom selected from the group consisting of N, O and S in the ring 
 or a salt, a hydrate, a hydrate of a salt or a solvate thereof. 
 
     
     
       3. The compound as claimed in  claim 1  or  2 
 in which 
 R 1  represents hydrogen, chlorine, nitro, methyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, where the alkoxy radicals for their part may be substituted by hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, —O—C(O)—CH 3  or cyclopropyl, or —NH—C(O)—CH 3 , 
 R 2  represents hydrogen 
 or 
 R 1  and R 2  are attached to adjacent phenyl ring atoms and represent a group —O—CH 2 —O—, 
 R 3  represents hydrogen, 
 R 4  represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, where the alkyl radicals for their part may be substituted by hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or cyclopropyl, or cyclopropyl, 
 R 5  represents methyl, ethyl, n-propyl, isopropyl, n-butyl, where the alkyl radicals for their part may be mono- or disubstituted, independently of one another, by cyclopropyl, phenyl, which for its pan may be substituted by fluorine, trifluoromethyl or methoxy, pyridyl, furyl or thienyl, ethenyl, propenyl or butenyl 
 and 
 R 6  represents methyl, ethyl, n-propyl, isopropyl, n-butyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl or isobutoxycarbonyl 
 or 
 R 5  and R 6  together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring
 or a salt, a hydrate, a hydrate of a salt or a solvate thereof. 
 
 
     
     
       4. A process for preparing compounds of the formula (I) as defined in  claim 1 , wherein either
 (A) a compound of the formula (II) 
 
       
         
           
           
               
               
           
         
         
           in which 
           R 1 , R 2  and R 3  are as defined in  claim 1  and X represents a leaving group, 
           is initially reacted with ethyl malonamide (III)
   H 2 N—C(O)—CH 2 —C(O)—O—C 2 H 5   (III) 
 
           to give a compound of the formula (IV) 
         
       
       
         
           
           
               
               
           
         
         
           in which 
           R 1, R   2  and R 3  are as defined in  claim 1 , 
           and then reacted with a compound of the formula (V)
   R 5 —Y  (V) 
 
           in which 
           R 5  is as defined in  claim 1  and Y represents a leaving group 
           to give a compound of the formula (I) 
           in which 
           R 1 , R 2 , R 3 , R 4  and R 5  are as defined in  claim 1  and R 6  represents a radical —C(O)—O—C 2 H 5 , 
           and, if appropriate, subsequently reacted with a compound of the formula (VI)
   R 8 —-OH  (VI) 
 
           in which R 8  is as defined in  claim 1   
           to give a compound of the formula (I) 
           in which 
           R 6  represents a radical —C(O)—O—R 8  and R 1 , R 2 , R 3 , R 4 , R 5  and R 8  are as defined in  claim 1 , 
         
         or 
         (B) a compound of the formula (II)
 is reacted with a Grignard compound of the formula (VII) 
 
       
       
         
           
           
               
               
           
         
         
           in which 
           R 5  and R 6  are as defined in  claim 1   
           to give a compound of the formula (I) 
           in which 
           R 1 , R 2 , R 3 , R 5  and R 6  are as defined in  claim 1  and R 4  represents hydrogen, 
           and, if appropriate, subsequently reacted wit a compound of the formula (VIII)
   R 4 —Y′  (VIII) 
 
           in which 
           R 4  is as defined in  claim 1  and Y′ represents a leaving group. 
         
       
     
     
       5. A pharmaceutical composition, comprising at least one compound of the formula (I) as defined in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       6. A method for the treatment of disorders of the cardiovascular system (cardiovascular disorders) comprising administering an effective amount of a compound of the formula (I) as defined in  claim 1 .